We have identified a pyruvate dehydrogenase kinase (PDK) inhibitor that is two orders of magnitude more potent than DCA in different cancer cell lines without exhibiting seizable cytotoxicity against healthy cells.

We are already writing a paper to report these results, but there are still a couple of loose ends that we would like to tie up prior to submission.

First of all, most of the "evidence" we have for pyruvate-site binding is computational and we need further empirical confirmation. Secondly, we would like to show that the activity in the cell-based assays correlates well with PDK inhibition in cell-free assays. We propose 5 experiments:

1.- We would like to measure PDK inhibition by our compound in cell-free assays for each of the four PDK isoforms. If our hypotheses are correct, our compound should inhibit primarily PDK1, moderately PDK2 and not at all PDK3. As for PDK4, according to our computational studies, should be closer to PDK1 than to PDK2.

2.- Next, we would like to express a single point Ile157Phe (PDK2 numbering) mutant of the most strongly inhibited isoform and assay that mutant to further confirm pyruvate-site binding.

If, for instance, PDK1 inhibition correlates better than the PDK2 inhibition (already determined by us) with the cell-based assays and both PDK3 and the mutant are essentially insensitive to inhibition, I believe we would have obtained enough evidence for the journals we are currently considering (Oncotarget and Molecular Cancer Therapeutics).

Do you have experience with PDK and /or PDC and would you be interested in helping us to get this paper ready for submission? Please, reply to this message or send me an e-mail ([email protected]) summarising your previous experience as well as the planned experimental approach and schedule.

We plan to use this publication as proof-of-concept in order to jointly apply for funding for a project aiming at the systematic exploration of the chemical space available at the pyruvate site of PDK.